C‐Myc‐mediated epigenetic silencing of MicroRNA‐101 contributes to dysregulation of multiple pathways in hepatocellular carcinoma. Issue 5 (27th March 2014)

• Record Type: Journal Article
• Authors: Wang, Lei; Zhang, Xiang; Jia, Lin‐Tao; Hu, Si‐Jun; Zhao, Jing; Yang, Jian‐Dong; Wen, Wei‐Hong; Wang, Zhe; Wang, Tao; Zhao, Jun; Wang, Rui‐An; Meng, Yan‐Ling; Nie, Yong‐Zhan; Dou, Ke‐Feng; Chen, Si‐Yi; Yao, Li‐Bo; Fan, Dai‐Ming; Zhang, Rui; Yang, An‐Gang
• Is Part Of: Hepatology. Volume 59:Issue 5(2014:May)
• Page Start: 1850
• Page End: 1863
• Publication Date: 2014-03-27
• Subjects: Heart -- Diseases -- Nursing -- Periodicals; Lungs -- Diseases -- Nursing -- Periodicals; Intensive care nursing -- Periodicals; Foie -- Maladies -- Périodiques; 616.362
• DOI: 10.1002/hep.26720
• Languages: English
• ISSNs: 0270-9139

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>The <italic>MYC</italic> oncogene is overexpressed in hepatocellular carcinoma (HCC) and has been associated with widespread microRNA (miRNA) repression; however, the underlying mechanisms are largely unknown. Here, we report that the c‐Myc oncogenic transcription factor physically interacts with enhancer of zeste homolog 2 (EZH2), a core enzymatic unit of polycomb repressive complex 2 (PRC2). Furthermore, miR‐101, an important tumor‐suppressive miRNA in human hepatocarcinomas, is epigenetically repressed by PRC2 complex in a c‐Myc‐mediated manner. miR‐101, in turn, inhibits the expression of two subunits of PRC2 (<italic>EZH2</italic> and <italic>EED</italic>), thus creating a double‐negative feedback loop that regulates the process of hepatocarcinogenesis. Restoration of miR‐101 expression suppresses multiple malignant phenotypes of HCC cells by coordinate repression of a cohort of oncogenes, including <italic>STMN1</italic>, <italic>JUNB</italic>, and <italic>CXCR7</italic>, and further increases expression of endogenous miR‐101 by inhibition of PRC2 activation. In addition, co‐overexpression of c‐Myc and EZH2 in HCC samples was closely associated with lower expression of miR‐101 (<italic>P</italic> < 0.0001) and poorer prognosis of HCC patients (<italic>P</italic> < 0.01). <italic>Conclusions</italic>: c‐Myc collaborates with EZH2‐containing PRC2 complex in silencing tumor‐suppressive miRNAs during hepatocarcinogenesis and provides promising therapeutic candidates for human HCC. (H<sc>epatology</sc> 2014;59:1850–1863)</p> </abstract>